CZ20024177A3 - Process for preparing 4-bromoaniline derivatives - Google Patents

Abstract

The invention relates to a method for producing 4-bromine-aniline derivatives of formula (I), wherein the substituents have the following meanings: R<1>: C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogen-alkoxy, C3-C8-cycloalkyl, halogen; R<2>: C1-C6-alkyl, C1-C6-alkoxy, C3-C8-cycloalkyl, C2-C6-alkenyl, cyano or a heterocyclic radical.

Description

Technical field

The present invention relates to a process for the preparation of 4-bromoaniline derivatives.

BACKGROUND OF THE INVENTION

4-Bromoaniline derivatives are useful compounds that are used as intermediates in the chemical industry. They are suitable, for example, for the preparation of active compounds used in the field of crop protection or for the preparation of pharmaceutically active compounds. For example, WO 99/58509 describes processes for preparing isoxazolin-3-yiacylbenzenes in which 4-bromoaniline derivatives are used as intermediates for the preparation of herbicidally active compounds. WO 98/31681 discloses these active compounds (2-alkyl-3- (4,5-dihydroisoxazol-3-yl) acylbenzenes) as herbicidally active compounds.

It is known in the literature that selective bromination of the anilines in the para position is impossible or only possible with difficulty (Houben-Weyl 5/4, 241, 274 ff). Generally, bromination with elemental bromine is not selective, but is often associated with the formation of a considerable amount of dibromo compounds. Experience has shown that the selectivity of monobromic compounds to dibromic compounds is of the order of about 9: 1, i.e. the proportion of undesirable dibromic compounds is about 10%. Thus, for example, 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline is obtained at -30 ° C in a yield of about 50% only using expensive reagents such as tetrabutylammonium bromide (see WO 99). / 58509).

Object of the invention

The present invention therefore relates to an alternative process for preparing 4-bromoaniline derivatives. The preparation method described in WO 99/58509 for 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline derivatives gives unsatisfactory yields and> unsatisfactory purity of the products. Consequently, the process described in WO 99/58509 is only of limited use for the industrial preparation of such compounds.

Applicants have found that this object can be achieved by a process for the preparation of 4-bromoaniline derivatives of formula (I)

in which:

R ¹ is C 1 -C ₆ -alkyl, C 1 -C ₆ -haloalkyl, C 1 -C ₆ -alkoxy, C ₁ -C ₆ -haloalkoxy, C ₃ -C ₈ -cycloalkyl, halogen,

R ² is C 1 -C ₆ -alkyl, C 1 -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, C ₂ -C ₆ -alkenyl, cyano or a heterocyclic radical which comprises the reaction of a compound of formula II

R .FČ

Wherein R ¹ and R ² are as described above, with a brominating agent in pyridine as a solvent or in a solvent mixture containing at least 55 wt. pyridine.

Using the process of the present invention, it is possible to obtain aniline derivatives of the general formula I in higher yields than the prior art processes. For example, 4-bromo-2- (4,5-dihydroisoxazol-3-yl) 3-methylaniline can be obtained by the method described in WO 99/58509 (see Example 10 therein) in a yield of only 47%, while the yield in the process according to the present invention it is at least 60%, preferably at least 70% or 80% and especially at least 90%.

In addition, the compounds of formula I are obtained with higher purity. There is bromination with high selectivity at the 4-position of the phenyl ring. The selectivity (ratio of monobromo compounds to dibromo compounds) is at least 92: 8, in particular at least 95: 5. Surprisingly, the proportion of impurities such as dibromides (these dibromides are derivatives of formula I that are substituted in the 5-position or 6-position with another bromine atom) that is difficult to remove from the resulting reaction mixture or whose removal requires relatively high engineering effort is less than 5%. . As a result, the number of additional additional purification steps for

β) »

The isolation and finishing of the compounds I prepared by the process of the present invention can be reduced. This is particularly advantageous in the industrial production of the compounds I, since an efficient and cost-effective production process can be achieved.

Due to the high selectivity and a small proportion of dibromo compounds, it is possible, if appropriate, to use the reaction product even without additional purification in the subsequent process steps for further conversion to suitable end products.

Hereinafter, the term C 1 -C 6 -alkyl means a straight or branched chain alkyl group having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or nhexyl; C 1 -C ₄ -alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl is preferred.

The term C1-C8-haloalkyl means a straight-chain or branched C1-C8-alkyl group as mentioned above, which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine atom (s), for example chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl , difluoromethyl;

995 ·· · ·

9 444

4 · · ·

Trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl,

2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl,

2.2.2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,

2.2.2- trichloroethyl, pentafluoroethyl, 2-fluoropropyl,

3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl,

2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl,

2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl,

3.3.3- trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl,

1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromoethyl,

4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl,

5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, β-fluorohexyl, 6-chlorohexyl, 6-bromohexyl,

6-iodo-hexyl or dodecafluorhexyl;

preferably C 1 -C ₄ -haloalkyl such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl,

2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl,

2.2.2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl,

2.2.2- trichloroethyl, pentafluoroethyl, 2-fluoropropyl,

3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl,

2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl,

2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl,

3.3.3- trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl,

1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromoethyl,

4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl.

The term C 1 -C 8 -alkoxy means a straight or branched chain alkyl group having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or nhexyloxy ; preferably C 1 -C ₄ -alkoxy such as methoxy, ethoxy, n-propyloxy, n-butyloxy, isobutyloxy or tert-butloxy.

The term C1-C8-haloalkoxy means a straight-chain or branched C1-C8-alkoxy group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine, for example fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy,

2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy,

2.2.2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy,

2.2.2- trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy,

3-fluoropropoxy, 2-chloropropoxy, 3-chloropropoxy,

2-bromopropoxy, 3-bromopropoxy, 2,2-difluoropropoxy,

2,3-difluoropropoxy, 2,3-dichloropropoxy,

3.3.3-trifluoropropoxy, 3,3,3-trichloropropoxy,

2.2.3.3- pentafluoropropoxy, heptafluoropropoxy,

1- (fluoromethyl) -2-fluoroethoxy, 1- (chloromethyl) 2-chloroethoxy, 1- (bromomethyl) -2-bromoethoxy, 4-fluorobutoxy,

4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy,

5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, i

,:

♦ ·· ·· · · · · · · · · · · · · · · · · · · · · · ·

5-Jepentoxy, undecafluoropentoxy, 6-fluorohexoxy,

6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably C 1 -C ₄ -haloalkoxy such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy,

2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2, difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy,

2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy,

3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy,

2,2-difluoropropoxy, 2,3-difluoropropoxy, 2,3-dichloropropoxy,

3.3.3-trifluoropropoxy, 3,3,3-trichloropropoxy,

2.2.3.3- pentafluoropropoxy, heptafluoropropoxy,

1- (fluoromethyl) -2-fluoroethoxy, 1- (chloromethyl) 2-chloroethoxy, 1- (bromomethyl) -2-bromoethoxy, 4-fluorobutoxy,

4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

The term C ₃ -C 8 -cycloalkyl means an unsubstituted or substituted cycloalkyl ring having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Suitable substituents are, for example, C 1 -C 6 -alkyl, C 1 -C ₆ -alkoxy or halogen atoms;

unsubstituted C ₃ -C 6 -cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl is preferred.

The term C 2 -C 6 -alkenyl means a straight or branched chain alkenyl group having 2-6 carbon atoms where the double bond is located at the point of attachment, such as, for example.

4 »

- 9 • 4 · 4

4 * ♦ 4 Ethenyl, prop-1-en-1-yl, 1-methylethenyl, buten-1-yl, 1-methylprop-1-en-1-yl, 2-methylprop-1-en-1-yl , penten-1-yl, 1-methylbut-1-en-1-yl, 2-methylbut-1-en-1-yl,

3-methylbut-1-en-1-yl, 1,2-dimethylprop-1-en-1-yl, hex-1-en-1-yl, 1-methylpent-1-en-1-yl, 2-methylpent- 1-en-1-yl

3-methylpent-1-en-1-yl, 4-methylpent-1-en-1-yl,

1,2-dimethylbut-1-en-1-yl, 1,3-dimethylbut-1-en-1-yl,

2,3-dimethyl-but-1-en-1-yl, 3,3-dimethyl-but-1-en-1-yl,

1-ethylbut-1-en-1-yl, 2-ethylbut-1-en-1-yl or 1-ethyl-2-methylprop-1-en-yl;

Halogen means fluorine, chlorine, bromine, especially chlorine or bromine.

The term heterocyclic ring means a saturated, unsaturated or partially unsaturated heterocycle having 3-8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms. Preferred are heterocycles which contain at least one oxygen atom and / or one nitrogen atom. In addition, heterocycles having 5 or 6 ring atoms are preferred. The heterocycle may be attached to the phenyl ring at any location in the heterocycle, for example, by a nitrogen atom of the heterocyclic ring or by a carbon ring atom. Heterocycles are unsubstituted or mono-, or trisubstituted. Suitable substituents are radicals that are chemically inert under the selected reaction conditions, such as, for example, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or a halogen atom. Suitable heterocyclic. the rings in the context of the present invention are, for example, the following heterocycles: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl;

4 »• 4 ** •« 4 «9 9 99

9 »· ·· ·

· 4 9

Isoxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, oxazinyl, isoxazolinyl, isoxazolidinyl and the like. Preferred are the following heterocycles: isoxazolyl, isoxazolinyl or isoxazolidinyl, especially

4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl.

The process of the present invention is suitable for the preparation of compounds of formula I wherein the substituents are defined as follows:

R ¹ is C 1 -C ₆ -alkyl, C 1 -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, halogen,

R ² is C 1 -C 8 -alkyl, C 1 -C 6 -alkoxy, C ₃ -C 8 -cycloalkyl, cyano or a heterocyclic radical.

The process according to the invention is furthermore suitable for the preparation of the following compounds of formula I:

4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline,

4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-ethylaniline,

4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methoxyaniline,

4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-ethoxyaniline, 4-bromo-2- (3-methyl-4,5-dihydroisoxazol-5-yl) 3-methylaniline,

4-Bromo-2- (3-methyl-4,5-dihydroisoxazol-5-yl) -3-ethylaniline, 4-bromo-2- (3-methyl-4,5-dihydroisoxazol-5-yl) 3-methoxyaniline ,

4-bromo-2- (3-methyl-4,5-dihydroisoxazol-5-yl) -3-ethoxyaniline,

8 «··· · • ·

4-bromo-2- (isoxazol-3-yl) -3-methylaniline,

4-bromo-2- (isoxazol-3-yl) -3-ethylaniline,

4-bromo-2- (isoxazol-3-yl) -3-methoxyaniline,

4-bromo-2- (isoxazol-3-yl) -3-ethoxyaniline,

4-bromo-2- (5-methylisoxazol-3-yl) -3-methylaniline,

4-bromo-2- (5-methylisoxazol-3-yl) -3-ethylaniline,

4-bromo-2- (5-methylisoxazol-3-yl) -3-methoxyaniline,

4-bromo-2- (5-methylisoxazol-3-yl) -3-ethoxyaniline,

4-bromo-2-cyano-3-methylaniline,

4-Bromo-2-cyano-3-methoxyaniline.

The reaction of the compounds II with the brominating agent is preferably carried out in the following steps:

According to the present invention, the reaction is carried out in pyridine as a solvent or in a solvent mixture containing at least 55% by weight, preferably 80% by weight, of pyridine. In the case of a solvent mixture, other solvents mixed with pyridine are suitable, for example, alcohols such as methanol or ethanol, especially methanol; esters such as ethyl acetate or butyl acetate, especially ethyl acetate or butyl acetate; amides such as N, N-dimethylformamide or N, N-dimethylacetamide; or water.

Initially, compound II is introduced into pyridine or a pyridine-containing solvent mixture in the form of a solution or suspension. The brominating agent is then added over a period of 5 minutes to 5 hours. The brominating agent is added either directly, i.e. without solvent, or together with a suitable solvent.

• * f · ·

A 9 9 9 9 10 11 12 13 12 13 14 15 16 17 18 19 20

Preferred brominating agents are elemental bromine or a mixture of HBr and hydrogen peroxide. In the case of bromine, bromine is preferably added together with a suitable solvent, such as pyridine, to form pyridinium perbromide. In this case, a particularly high selectivity of the ratio of monobromine compounds to dibromine compounds is achieved.

In a preferred embodiment of the process, the brominating agent and compound II are used in a molar ratio of from 1: 1 to 2: 1. The brominating agent is preferably used in equimolar amounts or in a slight excess.

The reaction is carried out at temperatures from 20 ° C to the boiling point of the solvent, preferably in the range from 60 ° C to 85 ° C. In another preferred embodiment, the reaction is carried out at a temperature of from 50 ° C to 100 ° C, preferably in the range of 80 ° C to 100 ° C, a particularly preferred temperature being about 100 ° C.

The reaction time is 1-24 hours, preferably 2-12 hours, especially 5-8 hours. In another preferred embodiment, the reaction time is 30 minutes - 10 hours, preferably 30 minutes hours.

If the brominating agent used is a mixture of HBr and hydrogen peroxide, the brominating agent is added to the solution of compound II over preferably from 10 minutes to 3 hours. The molar ratio of HBr to compound II is preferably in the range of 1: 1 to 1.5: 1. The addition is carried out at a temperature of from 0 to 50 ° C, preferably from 20 to 40 ° C. Hydrogen peroxide is then added. The molar ratio of Η ₂ Ο ₂ to HBr is from 1: 1 to 1.5: 1. The addition is carried out at temperatures from ♦ff ···· ff ffffff ffff ffffffff ff ff ff ffff f ffffff ffff f ffff ° C to the boiling point of the solvent, preferably from 50 ° C to 120 ° C, more preferably from 80 ° C to 100 ° C, particularly preferably at a temperature of about 100 ° C; in another preferred embodiment, the addition is preferably carried out at a temperature of from 60 ° C to 85 ° C. The solution is then stirred for 10 minutes to 36 hours, preferably 10 minutes 8 hours. In another embodiment, the solution is stirred for from 1 to 36 hours, preferably 2-8 hours. In another embodiment, the solution is stirred for from 10 minutes to 3 hours, preferably from 10 minutes to 2 hours. The product is then processed and purified. For this purpose, the solution is concentrated. The crude product is dissolved in a suitable solvent, preferably pyridine or a solvent mixture containing at least 50% pyridine, and water is added. Filtration and washing of the residue or crystallization using a suitable solvent (for example water) gives the product in good yield and high purity.

However, it is also possible to remove the crude product in dimethyl disulfide and wash the product with water and / or aqueous sodium hydroxide solution. The organic solution can then be used for subsequent steps.

In a preferred embodiment, the compound of formula (II) is initially introduced into pyridine or a mixture of pyridine and water. In the second case, the ratio of pyridine to water is in the range of 80 to 98 wt. % to 20 to 5 wt.%, preferably in the range 90 to 95 wt. to 10 to 5 wt.%.

The ratio of the compound of formula (II) to pyridine or pyridine / water is selected so as to form a 5-25% solution, preferably a 10-15% solution. Then, into the resulting solution

0 · 0 ·

0 · 0 ·

0 0 ·

0 0 «

0.000 to 0.0000 molar equivalents, preferably from 0.9 to 1.0 molar equivalents of HBr are added. The water is removed by azeotropic distillation and hydrogen peroxide is added to the solution, which remains for 1-3 hours, preferably 1.5-2.5 hours, at a temperature of 50-120 ° C, preferably 80-110 ° C, especially at a temperature of approximately Mp 100 ° C. The hydrogen peroxide is usually used in an aqueous solution at a concentration of 20% to 50%, preferably 30 to 50%.

The mixture is then stirred for about 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

This is followed by the final processing of the product. To this end, the reaction solution is cooled to approximately ambient temperature and, if desired, washed with an aqueous sodium sulfite solution and the organic phase is concentrated. The resulting product can be used without further purification for subsequent reactions. However, it is also possible to remove the residue in dimethyl disulfide, to wash the resulting solution with water or an aqueous sodium hydroxide solution and to use the resulting organic phase for subsequent reactions.

In another embodiment, it is possible to add HBr to pyridine, which, if appropriate, contains up to 10% water and then azeotropically removes the water. The compound of formula (II) is then dissolved in the reaction mixture and hydrogen peroxide is added dropwise. Both the quantitative ratios of the substances used and the time and temperature correspond to the above conditions.

·· ···· ···· *

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To ·

In another embodiment, pyridinium hydrobromide may also be used in place of pyridine and HBr.

If the brominating agent used is elemental bromine, the brominating agent is preferably added to the solution of compound II in portions or continuously over a period of about 30 minutes to 6 hours. The molar ratio of bromine to compound II is preferably in the range of 1: 1 to 1.5: 1. The addition is carried out at a temperature of from 0 to 50 ° C, preferably at ambient temperature. The solution is then stirred for 1-24 hours, preferably 2-8 hours. The product is then processed and purified. To this end, the solution is concentrated and the crude product is dissolved in a suitable solvent, preferably pyridine or a solvent mixture containing at least 50% pyridine and mixed with water. Filtration and washing of the residue or crystallization using a suitable solvent (e.g. water) gives the product in good yield and high purity.

In addition, the product can also be obtained from the reaction solution by extraction. To this end, the reaction solution is first concentrated and the residue is taken up in a suitable solvent or solvent mixture, the components of which are selected, for example, from water, ethyl acetate and dimethyl disulfide (DMDS), such as water, ethyl acetate, water / ethyl acetate or water / DMDS. Suitable for extraction are solvents which are not mixed with water or a mixture of the corresponding solvents, such as ethyl acetate, butyl acetate, toluene or methyl tert-butyl ether (MTBE). Concentration of the solution gives the product with good yield and high purity.

«« * · «3 ··

• 4 · · · · · · · ·

4 · 4

The crude product is purified by either washing the obtained residue or crystallizing. Suitable for washing are, for example, water and aqueous solvents. Suitable for recrystallization are, for example, toluene and benzene.

In principle, in the context of other responses, it is possible to; preparing the active compounds to use the obtained crude product in the next reaction step also without further purification of the reaction solution. To this end, the reaction solution containing the compounds of the formula I can be diluted with further solvents and thus used as a crude solution in the next step of the production process. Alternatively, it is also possible to concentrate the reaction solution and transfer the resulting residue directly or in the form of a melt to a further process step.

Compounds of formula II for use as starting materials are known in the literature and / or commercially available. Methods known per se can be prepared, such as those described in detail in WO 98/31681 or WO 99/58509.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further illustrated by the following examples.

Example 1

4 4

4 444

4444

4444

4-Bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline

Brominating agent: HBr / H ₂ O ₂

100.5 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline are initially taken up in 2000 g of pyridine and 98.2 g of HBr are added dropwise at 20-35 ° C. 64.6 g of hydrogen peroxide are then added dropwise at a temperature of 78-84 ° C over 0.5 hours. The mixture was stirred at 25 ° C for an additional 12 hours and then concentrated until an oily residue remained. The crude product is dissolved in 100 ml of pyridine at 50 ° C and mixed with 1000 ml of water. The mixture was stirred at 0 ° C for 1 hour and then filtered and the filter residue was washed twice with 200 ml of water and dried.

This gave 141 g (yield: 92%) of a yellow solid (HPLC: 94.6% of 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline,

1.8% 6-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 3.4% 4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) 3 - methylaniline).

Example 2

4-Bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline

Brominating agent: bromine

100 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline are initially taken up in 1000 g of pyridine and added dropwise.

0 ·· 0 solution of a total of 96.19 g of bromine in 1000 g of pyridine at 20 ° C in five freshly prepared batches and within 3 hours. The mixture was stirred for an additional 12 hours. The pyridine was distilled off at a pressure of 150 mbar and a bath temperature of 75 ° C. The residue is dissolved in 2 L of water and extracted repeatedly with 250 ml of ethyl acetate each time. Concentration gives 122.1 g of the product (yield 81.6%; GC: 93.2% 4-bromo-2- (4,5-dihydroisoxazol-3-yl) 3-methylaniline, 2.7% 6-bromo-2). - (4,5-dihydroisoxazol-3-yl) 3-methylaniline, 4.1% 4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline).

Example 3

4-Bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline

Brominating agent: bromine g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline is initially introduced into 50 g of pyridine and added dropwise at 20 ° C and over a period of 5 hours with a total of 4, 89 g of bromine in 50 g of pyridine (prepared at 0 ° C). The mixture was stirred at 25 ° C for an additional 12 hours. The batch is poured into 250 ml of water and extracted three times with 100 ml of MTBE each time. The combined organic phases are washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated.

Thus 6.0 g of the product are obtained (yield 79.8%; 94.3% of 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 1.8% of 6-bromo-2- (4, 4-bromo-2- (4,5-dihydroisoxazol-3-yl)). 5-dihydroisoxazol-3-yl) -3-methylaniline, 3.5%

4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline).

φφ φφφφ • φ

ΦΦ φ φ φ φ φ · φ · φ

Example 4

4-Bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline

Brominating agent: HBr, H2O2

500.0 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline are initially taken up in 4500 g of pyridine and 467.4 g of 47% HBr are added dropwise at 25-35 ° C. At the reflux temperature, water is azeotroped at atmospheric pressure. At 100 ° C, 199.2 g of 50% H ₂ O _{2 are} added dropwise over 2 hours. The reaction mixture was stirred for an additional hour and then cooled to ambient temperature and washed with sodium sulfite solution and the solvent was then distilled off (T < 100 ° C). The residue is taken up in 3220 g of dimethyl disulfide and washed at 1500C with 1500 g of water. The resulting solution is used for subsequent reactions.

This gives approximately 83% of the desired product.

Represented by:

JUDr. Otakar Švorčík

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JUDr. Otakar Švorčík attorney

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AA ··

Claims (10)

PATE Claims A process for preparing Formula I 4-bromoaniline derivatives of the general formula in which: R ^is _{C1-C6-alkyl, Ci-C6} haloalkyl, _Ci-C6 alkoxy, ΟχC6 ~ haloalkoxy, _C3-C8 cycloalkyl, halogen, R ² is C 1 -C ₆ -alkyl, C 1 -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, C ₂ -C 6 -alkenyl, cyano or a heterocyclic radical, characterized in that it comprises the reaction of a compound of formula II wherein R 2 ¹ and R ² are as stated above, with a brominating agent in pyridine as solvent. The process according to claim 1, wherein the brominating agent used is bromine. The process according to claim 1, wherein the brominating agent used is hydrogen bromide and hydrogen peroxide. Process according to any one of claims 1-3, characterized in that the solvent used is pyridine. A process according to any one of claims 1-4, wherein R ¹ is C 1 -C ₆ -alkyl. A process according to claim 5, wherein R ¹ is methyl or ethyl. A process according to any one of claims 1-6, wherein R ² is a heterocyclic ring. 0 0 0 0 0 0 00 0000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 · 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 · 0 0 8. The method according to claim 7, characterized in that R ² is ^an isoxazole, isoxazoline or isoxazolidine ring. The method of claim 8, wherein R ² is 4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl. Process according to any one of claims 1-8, characterized in that the substance to be prepared is 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline. Represented by: JUDr. Otakar Švorčík